Faculty Collaboration Database

A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia. J Hepatol 2023 Dec;79(6):1396-1407

Date

08/24/2023

Pubmed ID

37611641

Pubmed Central ID

PMC10841314

DOI

10.1016/j.jhep.2023.08.010

Scopus ID

2-s2.0-85173067427 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

BACKGROUND & AIMS: Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury.

METHODS: Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes.

RESULTS: A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device.

CONCLUSION: The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD.

IMPACT AND IMPLICATIONS: Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia.

Author List

de Jong IEM, Hunt ML, Chen D, Du Y, Llewellyn J, Gupta K, Li D, Erxleben D, Rivas F, Hall AR, Furth EE, Naji A, Liu C, Dhand A, Burdick JA, Davey MG, Flake AW, Porte RJ, Russo PA, Gaynor JW, Wells RG

Author

Mallory Hunt MD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bile Ducts, Extrahepatic
Biliary Atresia
Bilirubin
Child
Fetus
Humans
Mice
Rats
Sheep
Wound Healing